Method for the organometallic production of organic intermediate products comprising carbon-heteroatom bonds achieved by the deprotonation of heteroatoms

ABSTRACT

The invention relates to a method for binding heteroatom-carbon bonds. According to said method, a lithium compound (II) is first generated by reacting aliphatic or aromatic halogen compounds (I) with lithium metal, said compound is then used for the deprotonation of the compounds (III) or (V). The lithium salts of formulas (IV) or (VI) obtained by said deprotonation are subsequently reacted with suitable carbon electrophiles (equation I), said process binding the heteroatom-carbon bond and forming the products (VIII) or (VIII), (equation I).

The invention relates to a process for preparing organic compoundshaving carbon-heteroatom bonds, in which aliphatic or aromatic halogencompounds (I) are firstly reacted with lithium metal to generate alithium compound (II) which is then used to deprotonate the compounds(III) or (V), and the resulting lithium salts of the formula (IV) or(VI) are subsequently reacted with suitable carbon electrophiles to formthe heteroatom-carbon bond and produce the products (VIII) or (VIII)(EQUATION 1).Step 1: Generation of the base

Step 2: Deprotonation of the substrate

Step 3: Reaction with an electrophile

The upswing in organometallic chemistry, in particular that of theelement lithium, in the preparation of compounds for the pharmaceuticaland agrochemicals industries and also for numerous further applicationshas progressed almost exponentially in the past few years if the numberof applications or the quantity of products produced in this way isplotted against a time axis. Significant reasons for this are, firstly,the evermore complex structures of the fine chemicals required for thepharmaceuticals and agrochemicals sectors and, secondly, the virtuallyunlimited synthetic potential of organolithium compounds for building upcomplex organic structures.

A large part of this development has involved the use of organolithiumcompounds and alkali metal hydrides as strong bases having a lownucleophilicity for the deprotonation of alcohols, phenols, thiols,amines, etc., i.e. the generation of heteroatom anions, for reactionwith electrophiles.

The major part of this chemistry requires the use of commercialalkyllithium or aryllithium compounds, with n-butyllithium,methyllithium or phenyllithium most commonly being used here. Thesynthesis of such lithioaromatics and lithioaliphatics is technicallycomplicated and requires a great deal of know-how, as a result of whichmethyllithium, n-butyllithium, s-butyllithium, tert-butyllithium,phenyllithium and similar molecules are, from an industrial viewpoint,offered at very high prices. This is the most important but far from theonly disadvantage of these otherwise very advantageous and widely usablestrong bases. Although alkali metal hydrides are cheaper, they have,owing to their considerably lower basisity, the disadvantage of aconsiderably smaller range of applications.

Owing to the extreme sensitivity and, in concentrated solutions,pyrophoric nature of organolithium compounds, very costly logisticssystems for transport, introduction into the metering reservoir andmetering are required for the large amounts (annular productionquantities of from 5 to 500 metric tons) wanted in large-scaleindustrial production. A similar situation applies to the alkali metalhydrides which are likewise pyrophoric in pure form and are frequentlystabilized with mineral oil. The processing of these solids which have avery poor solubility in organic solvents under the relevant conditionsis a problem which has not really been solved in industry.

Furthermore, the deprotonation of H-acidic compounds by means ofmethyllithium forms methane gas and the use of n-, s- andtert-butyllithium forms butanes which are likewise gaseous at roomtemperature and are given off during the reaction or in the necessaryhydrolytic work-ups of the reaction mixture. As a result, complicatedoffgas purifications or appropriate incineration facilities are alsonecessary in order to meet strict pollution laws. As a way of avoidingthis, specialist companies are offering alternatives such asn-hexyllithium which do not result in formation of butanes, but aresignificantly more expensive than butyllithium. The use ofphenyllithium, on the other hand, leads to formation of the humancarcinogen benzene, which frequently rules out industrial use.Alternatives such as 4-tolyllithium are very difficult to obtain on themarket, especially not in the volume required for production tasks.

Even greater difficulties than those posed by the lower alkyllithiumcompounds are presented by the use of alkali metal hydrides, since theiruse results in the formation of hydrogen which, particularly at hightemperatures, can lead not only to exhaust air problems (danger offormation of explosive hydrogen/oxygen mixtures) but also to damage tomaterials, e.g. embrittlement of metals caused by diffusion andincorporation.

A further disadvantage is that complex solvent mixtures are obtainedafter the work-up. Owing to the high reactivity of organolithiumcompounds toward ethers, which are virtually always used as solvents forthe subsequent reactions, alkyllithium compounds can usually not bemarketed in these solvents. Producers do offer a broad range ofalkyllithium compounds in a wide variety of concentrations in a widevariety of hydrocarbons and ether/hydrocarbon mixtures, but hydrolysisresults in water-containing mixtures of ethers and hydrocarbons whoseseparation is complicated and can in many cases not be carried outeconomically at all. This likewise applies to the mineral oil in whichthe alkali metal hydrides are usually supplied. However, recycling ofthe solvents used is an indispensable prerequisite for large-scaleindustrial production.

For the reasons mentioned, it would therefore be very desirable to havea process in which an alkyllithium compound to be used fordeprotonation, which as far as possible overcomes the disadvantagesmentioned, is generated from the cheap raw materials haloalkane orhaloaromatic and lithium metal in an ether and reacted simultaneously orsubsequently with the substrate to be deprotonated, since this procedurecan overcome all the abovementioned disadvantages of the “classical”generation of the lithium compounds mentioned.

The present invention achieves all these objects and provides a processfor forming heteroatom-carbon bonds, in which aliphatic or aromatichalogen compounds (I) are firstly reacted with lithium metal to generatea lithium compound (II), this is then used for deprotonating thecompounds (III) of (V), and the resulting lithium salts of the formula(IV) or (VI) are finally reacted with suitable carbon electrophiles toform the heteroatom-carbon bond and produce the product (VIII) or (VIII)(equation I).Step 1: Generation of the base

Step 2: Deprotonation of the substrate

Step 3: Reaction with an electrophile

Here, R is methyl, a primary, secondary or tertiary branched orunbranched alkyl radical having from 1 to 20 carbon atoms, a phenyl,aryl or heteroaryl radical, alkyl substituted by a radical from thegroup consisting of {methyl, primary, secondary or tertiary alkyl,phenyl, substituted phenyl, aryl, heteroaryl, alkoxy, dialkylamino,alkylthio}, substituted or unsubstituted cycloalkyl having from 3 to 8carbon atoms,

-   Hal=fluorine, chlorine, bromine or iodine,-   X₁ is an oxygen or sulfur bound via a single bond to R1 or an    sp2-hybridized nitrogen bound via a double bond to R1, and X₂ is an    sp3-hybridized nitrogen, the radicals R₁ and R₂ are each,    independently of one another, a substituent selected from the group    consisting of {hydrogen, methyl, primary, secondary or tertiary,    cyclic or acyclic alkyl, alkenyl or alkynyl radicals having from 1    to 20 carbon atoms, substituted cyclic or acyclic alkyl groups, acyl    groups, alkoxy, aryloxy, dialkylamino, alkylamino, arylamino,    diarylamino, alkylarylamino, imino, sulfone, sulfonyl, phenyl,    substituted phenyl, alkylthio, diarylphosphino, dialkylphosphino,    alkylaryl-phosphino, dialkylaminocarbonyl or diarylaminocarbonyl,    monoalkylamino-carbonyl or monoarylaminocarbonyl,    alkylarylaminocarbonyl, alkoxyalkyl, carboxylate, alkylcarboxylate,    CN or CHO, heteroaryl}, where two adjacent radicals R₁ and R₂ can    together correspond to an aromatic or aliphatic ring.

Preferred compounds of the formula (III) which can be reacted by theprocess of the invention are, for example, alcohols, thiols, phenols,thiophenols, oximes, hydrazones, and preferred compounds of the formula(V) are, for example, amines, carboxamides, sulfonamides and hydrazines,to name only a few.

The organolithium compounds prepared in this way can be reacted with anyelectrophilic compounds by methods of the prior art. For example,alkylations to produce ethers, thioethers, secondary and tertiaryamines, etc., can be carried out by reaction with carbon electrophiles,or hemiacetals and their downstream produces and also esters, acidamides and carbonyl derivatives can be prepared by carbonyl additions.

The carbon electrophiles come, in particular, from one of the followingcategories (the product groups are in each case shown in brackets):

-   aryl or alkyl cyanates, isocyanates (carbonic acid derivatives)-   oxirane, substituted oxiranes (2-hydroxy ethers, amines, thioethers,    etc.)-   aziridines, substituted aziridines (2-amino ethers, amines,    thioethers, etc.)-   imines, aldehydes, ketones (hemiacetals, hemiaminals,    hemithioacetals, etc.)-   organic halogen compounds, triflates, other sulfonates, sulfates    (substitution products/alkylation products)-   ketenes (carboxylic acid derivatives)-   carboxylic acid chlorides (carboxylic acid derivatives)-   carboxylic esters, thioesters and amides (carboxylic acid    derivatives)-   carbonic esters and phosgene derivatives (carboxylic acid    derivatives)

As haloaliphatics or haloaromatics, it is possible to use all availableor procurable fluorine, chlorine, bromine or iodine compounds, sincelithium metal reacts readily with all haloaromatics and haloaliphaticsin ether solvents, giving quantitative yields in virtually all cases.Preference is given here to using chloroaliphatics or bromoaliphatics,since iodo compounds are often expensive and fluorine compounds lead tothe formation of LiF which can, as HF, lead to material problems in thelater aqueous work-ups. In specific cases, however, such halides mayalso be able to be used advantageously.

In the process of the invention, preference is given to using alkyl oraryl halides which, after deprotonation, can be reacted to produceliquid alkanes or aromatics. Particular preference is given to usingchlorocyclohexane or bromocyclohexane, benzyl chloride, tert-butylchloride, chlorohexanes, chloroheptanes or chlorooctanes and alsochlorobenzenes and bromobenzenes, chlorotoluenes and bromotoluenes andchloroxylenes and bromoxylenes.

The reaction is carried out in a suitable organic solvent, preferably anether solvent such as tetrahydrofuran, dioxane, diethyl ether,di-n-butyl ether, glyme, diglyme, dibutyidiglyme or anisole. Particularpreference is given to using tetrahydrofuran.

A further advantage of the process of the invention is that it can becarried out at quite high concentrations of organolithium compounds.Preference is given to concentrations of the aliphatic or aromaticintermediates of the formula (II) of from 5 to 30% by weight, inparticular from 12 to 25% by weight.

In the preferred embodiment, halogen compound (R-Hal) and substrate tobe deprotonated (III or IV) are added simultaneously or as a mixture tothe lithium metal in the ether. In this one-pot variant, theorganolithium compound is formed first and then immediately deprotonatesthe substrate. However, it is also possible (and especially appropriatewhen the substrate can undergo secondary reactions with metallic lithiumfirstly to generate the organolithium compound in ether by reaction ofthe halogen compound and lithium and only then add the substrate.

Owing to the high reactivity of the alkyllithium and aryllithiumcompounds, in particular toward, inter alia, the ethers used assolvents, the preferred reaction temperatures are in the range from −100to +70° C.; particular preference is given to temperatures of from −80to −25° C. if the deprotonation is not carried out simultaneously withthe lithiation but in a second step. In the variant with simultaneouslithiation and deprotonation, the particularly preferred temperaturerange is from −40 to +40° C.

We have surprisingly found that in the preferred embodiment as a one-potreaction, significantly higher yields and shorter reaction times thanwhen RLi is generated first and the substrate to be deprotonated is onlyadded subsequently are observed in many cases.

In the present process, the lithium can be used as dispersion, powder,turnings, sand, granules, pieces, bars or in another form, with the sizeof the lithium particles not being relevant to quality but merelyinfluencing the reaction times. Preference is therefore given torelatively small particle sizes, for example granules, powders ordispersions. The amount of lithium added per mole of halogen to bereacted is from 1.95 to 2.5 mol, preferably from 1.98 to 2.15 mol.

In all cases, significant increases in the reaction rates can beobserved when organic redox systems, for example biphenyl,4,4′-di-tert-butyl-biphenyl or anthracene, are added. The addition ofsuch systems has been found to be particularly advantageous when thelithiation times without this catalysis would be >12 hours.

Substrates which can be used for the deprotonation are firstly alloxygen, sulfur and nitrogen compounds which on the respective heteroatombear a hydrogen atom which is sufficiently acidic to be deprotonatedunder the reaction conditions.

Mention may here be made, first and foremost, of all alcohols, thiolsand nontertiary amines. The basisity of the organolithium compoundformed is in virtually all cases sufficient to deprotonate thesecompounds. Compounds which are particularly easy to deprotonate arecompounds (III) or (V) having groups R1 and R2 which are able tostabilize the resulting negative charge by mesomeric and/or inductiveeffects. This is the case for, for example, carboxyamides, arylamines,phenols, thiophenols, naphthols and also conjugated oximes, hydrazones,etc.

The lithium compounds generated according to the invention can bereacted with electrophilic carbon compounds (electrophiles) by methodswith which those skilled in the art are familiar to give products havingnewly formed heteroatom-carbon bonds, which are of great interest forthe pharmaceutical and agrochemicals industries.

The work-ups are generally aqueous, with either water or aqueous mineralacids being added or the reaction mixture being introduced into water oraqueous mineral acids. To achieve the best yields, the pH of the productto be isolated is in each case set. The reaction products are obtained,for example, by extraction and evaporation of the organic phases, or, asan alternative, the organic solvents can also be distilled off from thehydrolysis mixture and the product which then precipitates can beisolated by filtration.

The purities of the products from the process of the invention aregenerally high, but a further purification step, for example byrecrystallization with addition of small amounts of activated carbon,may be necessary for special applications (pharmaceutical precursors).The yields of the reaction products are from 70 to 99%; typical yieldsare, in particular, from 85 to 95%.

The process of the invention provides a very economical method ofbringing about the transformation of an aromatic hydrocarbon into anyradicals in a highly selective, economical way.

The process of the invention is illustrated by the following examples,without the invention being restricted thereto.

EXAMPLE 1 Preparation of 2-furylmethyl propargyl ether fromfurylmethanol and propargyl bromide (two-step procedure)

A suspension of 1.45 g (0.210 mmol) lithium granules in 170 ml oftetrahydrofuran is cooled to −35° C. and slowly admixed with 13.29 g(0.105 mol) of 4-chlorotoluene. Stirring is continued at thistemperature until the conversion of the 4-chlorotoluene is at least 97%a/a according to GC (about 8 hours). 9.81 g (0.100 mol) of2-furylmethanol are added, the mixture is allowed to warm to roomtemperature, 14.28 g (0.120 mol) of propargyl bromide are added and themixture is refluxed for 2 hours. After cooling, the reaction mixture isshaken with 100 ml of 2N hydrochloric acid and the phases are separated.The aqueous phase is reextracted twice with 50 ml each time of toluene,the combined organic phases are evaporated and the crude product isdistilled under reduced pressure at up to 70° C. via a Vigreux column.This gives 12.66 g (0.093 mol, 93%) of 2-prop-2-yloxymethylfuran in anHPLC purity of >97% a/a.

EXAMPLE 2 Preparation of methylN′-benzylidene-N-phenylhydrazinecarboxylate (acylation of benzaldehydephenylhydrazone, one-pot variant)

A suspension of 1.45 g (0.210 mol) of lithium granules in 150 ml oftetrahydrofuran and 19.63 g (0.100 mol) of benzaldehyde phenylhydrazoneis admixed at −40° C. with 15.61 g (0.105 mol) of octyl chloride and themixture is stirred at −30° C. until the conversion of the octyl chlorideaccording to GC is at least 97% a/a (about 8 hours). 11.34 g (0.120 mol)of methyl chloroformate are then added dropwise and the reaction mixtureis stirred at 0° C. for 30 minutes. The reaction mixture is hydrolyzedwith 100 ml of water, the phases are separated and the aqueous phase isextracted three times with 50 ml each time of toluene. The combinedorganic phases are evaporated and the crude product is recrystallizedfrom ethanol. The product is obtained in the form of colorless,platelet-like crystals in a yield of 20.85 g (0.082 mol, 82%) and anHPLC purity of >98.5% ala.

EXAMPLE 3 Preparation of methyl N,N-diphenylcarbamate from diphenylamine(one-pot variant, catalyzed lithiation)

16.92 g (0.100 mol) of diphenylamine, 25 mg of biphenyl as redoxcatalyst and 1.45 g (0.105 mol) of lithium granules are added to 150 mlof tetrahydrofuran and the resulting suspension is cooled to −25° C.13.29 g (0.105 mol) of 4-chlorotoluene are added dropwise over a periodof 60 minutes. Stirring is continued until monitoring of the conversionby GC indicates a conversion of >97% a/a (about 4 hours), and 11.34 g(0.120 mol) of methyl chloroformate are then added dropwise to thereaction mixture. The reaction mixture is warmed to room temperature,the solvent and unreacted chloroformic ester are distilled off and theresidue is fractionated via a short column. This gives 19.77 g (0.087mol, 87%) of methyl N,N-diphenylcarbamate.

EXAMPLE 4 Preparation of dihexyl thioether from hexanethiol andbromohexane

1.45 g (0.105 mol) of lithium granules are suspended in a solution of 50mg of biphenyl in 150 ml of tetrahydrofuran. At −30° C., 13.29 g (0.105mol) of the technical-grade mixture of monochlorotoluene isomers areadded dropwise and the reaction mixture is stirred at this temperatureuntil the lithium granules have largely dissolved (about 6 hours). 11.82g (0.100 mol) of hexanethiol are then added dropwise, the reactionmixture is warmed to 0° C., 16.51 g (0.100 mol) of bromohexane are addedand the mixture is refluxed until monitoring of the conversion by GCindicates complete reaction. The cooled reaction mixture is extractedwith 50 ml of water, the aqueous phase is reextracted with 50 ml oftoluene and the combined organic phases are evaporated. The residue isdistilled under reduced pressure. This gives 17.81 g (0.085 mol, 85%) ofdihexyl thioether having a GC purity of >98%.

EXAMPLE 5 Preparation of benzyl N-benzyl-N-benzenesulfonylcarbamate fromN-benzylbenzenesulfonamide

13.29 g (0.105 mol) of 4-chlorotoluene are added dropwise to asuspension of 1.45 g (0.210 mol) of lithium granules in 150 ml oftetrahydrofuran and 24.73 g (0.100 mol) of N-benzylbenzenesulfonamide at−40° C. and the mixture is stirred at this temperature until theconversion of the tolyl chloride according to GC is at least 97% a/a(about 6 hours). 11.34 g (0.120 mol) of benzyl chloroformate are thenadded dropwise and the reaction mixture is stirred overnight at roomtemperature. The reaction mixture is hydrolyzed with 100 ml of water,the phases are separated and the aqueous phase is reextracted with 100ml of toluene. The combined organic phases are evaporated and theresidue is purified by flash chromatography. This gives 26.30 g (0.069mol, 69%) of the product having an HPLC purity of >96%

1. A process for forming heteroatom-carbon bonds, said processcomprising reacting in a reaction mixture aliphatic or aromatic halogencompounds (I) with lithium metal to generate a lithium compound (II),deprotonating the compounds (III) or (V) by reaction with the lithiumcompound (II), and reacting the resulting lithium salts of the formula(IV) or (VI) with a suitable carbon electrophile to form theheteroatom-carbon bond and produce the product (VIII) or (VIII)(equation 1). Step 1: Generation of the base

Step 2: Deprotonation of the substrate

Step 3: Reaction with an electrophile

where, R is methyl, a primary, secondary or tertiary branched orunbranched alkyl radical having from 1 to 20 carbon atoms, a phenyl,aryl or heteroaryl radical, alkyl substituted by a radical selected fromthe group consisting of methyl, primary, secondary or tertiary alkyl,phenyl, substituted phenyl, aryl, heteroaryl, alkoxy, dialkylamino,alkylthio, substituted or unsubstituted cycloalkyl having from 3 to 8carbon atoms, and mixtures thereof; Hal is a halogen selected from thegroup consisting of fluorine, chlorine, bromine, iodine, and mixturesthereof, X₁ is an oxygen or sulfur bound via a single bond to R1 or ansp2-hybridized nitrogen bound via a double bond to R1, and X₂ is ansp3-hybridized nitrogen; the radicals R₁ and R₂ are independently of oneanother substituents selected from the group consisting of hydrogen,methyl, primary, secondary or tertiary, cyclic or acyclic alkyl, alkenylor alkynyl radicals having from 1 to 20 carbon atoms, substituted cyclicor acyclic alkyl groups, acyl groups, alkoxy, aryloxy, dialkylamino,alkylamino, arylamino, diarylamino, alkylarylamino, imino, sulfone,sulfonyl, phenyl, substituted phenyl, alkylthio, diarylphosphino,dialkylphosphino, alkylarylphosphino, dialkylaminocarbonyl ordiarylaminocarbonyl, monoalkylaminocarbonyl or monoarylaminocarbonyl,alkylarylaminocarbonyl, alkoxyalkyl, carboxylate, alkylcarboxylate, CN,CHO, heteroaryl and mixtures thereof, where two adjacent radicals R₁ andR₂ can together correspond to an aromatic or aliphatic ring.
 2. Theprocess as claimed in claim 1, wherein the compounds of the formula(III) are selected from the group consisting of alcohols, thiols,phenols, thiophenols, oximes, hydrazones, and mixtures thereof, and thecompounds of the formula (V) are selected from the group consisting ofamines, carboxamides, sulfonamides, hydrazines, and mixtures thereof. 3.The process of claim 1, wherein the electrophile is selected from thegroup consisting of aryl or alkyl cyanates, isocyanates, oxirane,substituted oxiranes, aziridines, substituted aciridines, imines,aldehydes, ketones, organic halogen compounds, triflates, othersulfonates, sulfates, ketenes, carboxylic acid chlorides, carboxylicesters, thioesters and amides, carbonic esters, phosgene derivatives,and mixtures thereof.
 4. The process of claim 1, wherein the reaction iscarried out in an organic ether solvent.
 5. The process of claim 1,wherein said reacting step is carried out at a reaction temperature inthe range from −100 to +70° C.
 6. The process of claim 1, wherein aconcentration of aliphatic or aromatic intermediates of the formula (II)are in the range from 5 to 30% by weight.
 7. The process of claim 1,wherein lithium metal is added in an amount per mole of halogen reactedranging from 1.95 to 2.5 mol.
 8. The process of claim 1, furthercomprising adding organic redox systems to the reaction mixture.